This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Botulinum neurotoxins (BoNTs) pose a biological hazard to humans and are classified as Class-A bioterrorism threat agents by Centers for Disease Control (CDC). They are composed of seven different serotypes named BoNT/A-G. BoNTs bind with high specificity at neuromuscular junctions (NMJs) and they impair exocytosis of synaptic vesicles containing acetylcholine through specific proteolysis of SNAREs (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors), which constitute part of the synaptic vesicle fusion machinery. Subsequently, BoNTs inhibit motor neuron activity and thus breathing, resulting in respiratory arrest. Surprisingly, some serotypes of BoNT will not only paralyze neurons but also cause neurite loss and ultimately lead to neuronal apoptosis (neurodegeneration). We propose to study the mechanism of action of BoNTs in order to better characterize its role in neurodegeneration and to develop inhibitors to treat and prevent this new form of BoNT injury.